3.

THE RELATION OF THE PHOSPHATIDS TO OVERTON

AND MEYER'S THEORY OF NARCOSIS

w. KOCH AND F. C. McLEAN

The older theories of narcosis have been so well reviewed in

Overton's' book as not to require further mention. Overton
and Meyer's2 hypothesis, arrived at independently, that the nar
cotic power of a substance is dependent on its distribution co
efficient between oil and water is too well known to require detailed
description. The more recent attempt of Traube3 to bring the
property of a good many narcotics to produce changes of surface
tension into relation with the phenomenon of narcosis is not su.ffi
ciently general. Thus the very striking relationships which Meyer
discovered in the suffonal series cannot be accounted for by any
changes in surface tension. The work of Moore and Roaf4 on the
action of chloroform on proteins need hardly be taken seriously,
as they used concentrations which were much above the con
centration of chloroform ever to be expected in the tissues during
narcosis. The lack of regard for such quantitative relationships
is a very common source of error in pharmacological investiga
tions of this type.
The present investigation was undertaken with the purpose of
establishing, if possible, an experimental basis for the suggestion
implied in both Overton and Meyer's work, namely, that changes
in the physical state of the phosphatids may account for the
phenomenon of narcosis. To demonstrate this required the inves
tigation of the following points:

‘¿Overton:
Theorie der Narcose.
2 Meyer, H.: Archiv. f. exper. Pharm. and Path., 1899, xlii, 109 and 119 and

1901, xlvi, 338 and 347.

$ Traube, J.: Pflugers Archiv. 1904, cv, 541 and 559, and 1908, cxxiii, 419.

Moore, B. and Roaf,H. E.: Proc.Royal Soc.B.,1905,lxxvii,

90.
250 w. KOCH AND F. C. McLEAN

1. Can changes in the state of aggregation of the phosphatids,

provided they are produced by anaesthetics and narcotics, be
made to account for the phenomenon of narcosis?
2. Is there any evidence that the anaesthetics enter into com
bination with the phosphatids or produce changes in their state.
of aggregation?
The two chemical substances which produce the most marked
changes in the state of aggregation of the phosphatids are acids and
alkali, as has already been pointed out in a previous communica
tion.@ Acids increase the surface tension and cause the formation
of larger aggregates, thus decreasing the amount of calcium
required to precipitate. Physiologically acids produce a condi
tion of decreased irritability which may bear some relation to the
phenomenon of narcosis. Alkalies decrease the surface tension
and cause the formation of smaller aggregates, thus increasing
the amount of calcium required to precipitate. Physiologically
alkalies, if not used in too great concentration, have a tendency
to produce a condition of increased irritability. From these
considerations one might expect the anaesthetics and narcotics
to resemble the acids in their action. In the following table a
number of substances were arranged with regard to their ability
to change the state of aggregation of a 0.15 per cent emulsion of
brain lecithin, as determined by the amount of calcium chloride
required to produce a precipitate:

TABLE I

INCREASE IN SIZE OF COLLOIDAL. . NO CHANGE INCREASE IN SIZE OF COLlOIDAL

PARTICLES' PARTICLESt

Acids ChioralAlkaliesHypnonChloroformAcetoneSulfonalEther
Alcohol
Triacetin
Paraldehyde (pure)Ammonia
Ether (impure) Bile Salts

‘¿Exceptin the case of acids the amount of change with the substances of the first column is very
slight and can just about be detected.
tThe change produced by the substance of this column is very conlderable (see 4) Koch and
Williams.

‘¿Koch,W., Zeitschrift fürphysiologische Chemie., 1909, lxiii, 432.

@ - -@,,.@w -@
.@ I

RELATION OF THE PHOSPHATIDS TO NARCOSIS 251

The absence of any relation between changes in physical state

of aggregation and the power of the above substances to act as
narcotics or anaesthetics is so plainly apparent, that it was not
considered worth while to extend the above table. One point is,
however, of considerable interest ; namely, the difference between
chloroform and pure ether, which produces no change. If we
interpret the decrease in size of particles as evidence of one kind
of chemical combination we have here an explanation of the slower
rate at which chloroform is eliminated from the tissues and its
consequent tendency to produce delayed poisoning. In order to
make certain that the small amounts of chloroform which can be
demonstrated to be actually present in the tissues during anaes
thesia, are capable of producing this change, the action of chloro
form was investigated more in detail.
Experiment: 100 cc. of a 0.3 per cent emulsion of brain lecithin
was shaken for one hour with 1 gram of chloroform. The pre
cipitation limit of this emulsion was then compared with a con
trol (0.3 per cent) solution of lecithin. The chloroform solution
required for precipitation a concentration of 0.0027 m. CaC12
while the control required 0.0015 m. CaCl2, a difference of 1.2 cc.
expressed in 0.01 m@ The chloroform lecithin emulsion was
then diluted with lecithin emulsion to determine the smallest
quantity of chloroform which has any appreciable effect. The
results are given in the following table and also plotted in the
form of a curve:
TABLE II

CHLOROFORM CaCi, to PPT. CONTROL EXCESS OP CaCI:

per cent. in. in. in.

0.5 0.0027 - 0.0015 0.0012
0.375 0.0022 - 0.0015 0.0007
- 0.25 0.0019 . 0.0015 0.0004

0.188 0.0018 0.0015 0.0003

0.125 0.0017 0.0015 0.0002
0.063 0.0016 0.0015 0.0001 -
0.000 0.0015 0.0015 0.0000

The lowest concentration of chloroform which produced a notice

able effect was 0.063 per cent, an amount which has actually
 252 W. KOCH AND F. C. McLEAN

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been found by several investigators to be present in tissues during

chloroform narcosis.
Some experiments were tried with kephalin emulsions, and
they yielded similar but less striking results.
SUMMARY

There is no evidence that. anaesthetics or hypnotics produce

changes in the state of aggregation of lecithin or kephalin, which
are sufficiently consistent, to account for such a general phe
nomenon as narcosis. There is some evidence, however, that chlo@
roform as distinguished from pure ether has the power to form a
combination with lecithin, a phenomenon which may be brought
into relation with its slow elimination and consequent tendency
to produce delayed poisoning.